PROJECT SUMMARY Traumatic brain injuries (TBI), including concussions, are an area of significant unmet need with no approved therapeutics and a national burden of ~$77 billion annually. TBI is the global leading cause of post-injury death and disability, and over 2 million Americans sustain a TBI each year. The tremendous incidence and long-term consequences of TBI highlight the considerable epidemic at hand, and the need for neuroprotective treatments. Astrocyte Pharmaceuticals Inc. is developing a proprietary small molecule pharmaceutical agent for acute administration to TBI patients that will dramatically improve the survival of neurons, affected brain tissue, and the long-term neurological deficits that have been linked to TBI. The proprietary approach at Astrocyte Pharmaceuticals differs significantly from historical neuroprotective attempts in that it focuses on a non-neuronal cell type, the astrocyte, which has only recently received broader attention as an important cellular target for successful therapeutic research. Molecular activation of astrocytes enhances multiple healing mechanisms including protection against edema, glutamate excitotoxicity and oxidative stress. Phase I studies identified a lead candidate, AST-004, which demonstrates significant neuroprotective benefits in murine and porcine TBI models without side effects at a reasonable dosing regimen. The goal of this SBIR Phase II project is to advance this promising TBI therapeutic to an IND and a first-in-human Phase I clinical trial through the completion of critical path preclinical activities. The project aims to (1) perform FDA-required toxicology and safety pharmacology studies in rats and dogs, (2) conduct required in vitro studies to characterize AST-004's liver metabolism and potential for drug-drug interactions, and (3) develop the manufacturing process for the IV formulation of AST-004 and manufacture drug product for a first-in-human clinical trial. Successful completion of this project will lead to an IND submission with the FDA and a subsequent first-in-human Phase I clinical trial.